Fungicidal 5-phenyl substituted 2-(cyanoamino) pyrimidines

ABSTRACT

Pyrimidines of formula I                    
     in which 
     R 1  represents hydrogen or alkyl, haloalkyl, alkenyl, alkynyl, alkadienyl, alkoxy, cycloalkyl, phenyl, or 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl, containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom, or tri-alkyl-silyl, formyl or alkoxycarbonyl, 
     wherein R 1  groups are unsubstituted or substituted as defined in the specification; 
     R 2  represents phenyl, cycloalkyl or 5- or 6-membered heteroaryl, containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom, which are unsubstituted or substituted; 
     R 3  represents hydrogen, halogen or alkyl, alkoxy, alkylthio, alkylamino or dialkylamino; which are unsubstituted or substituted; 
     R 4  represents hydrogen or alkyl, alkenyl or alkynyl; which are unsubstituted or substituted; and 
     X represents O, S, NR 5  or a single bond, wherein R 5  represents hydrogen or alkyl; or 
     R 1  and R 5  together with the interjacent nitrogen atom form a heterocyclic ring; 
     processes and intermediates for preparing these compounds, to compositions comprising them and to their use for controlling harmful fungi.

This application claims the benefit under 35 USC 119(e) of U.S.provisional applications 60/211,262 filed Jun. 13, 2000 and 60/231,632filed Sep. 11, 2000.

The present invention relates to pyrimidines of formula I

in which

R¹ represents hydrogen or

C₁-C₁₀-alkyl, C₁-C₁₀-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₄-C₈-alkadienyl, C₁-C₁₀-alkoxy, C₃-C₈-cycloalkyl, phenyl, or

5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl, containingone to four nitrogen atoms or one to three nitrogen atoms and one sulfuror oxygen atom, or

tri-C₁-C₆-alkyl-silyl, formyl or C₁-C₁₀-alkoxycarbonyl;

wherein R¹ groups are unsubstituted or substituted by one to threegroups R^(a)

R^(a) halogen, nitro, cyano, hydroxy or

C₁-C₁₀-alkyl , C₃-C₆-cycloalkyl, C₃-C₆-cycloalkenyl, C₁-C₁₀-haloalkyl,C₃-C₆-halocycloalkyl, C₁-C₁₀-alkoxy, C₁-C₁₀-haloalkoxy,C₁-C₁₀-haloalkoxy, C₁-C₆-alkoxycarbonyl, tri-C₁-C₄-alkylsilyl, phenyl,halo- or dihalo-phenyl or 5- or 6-membered heteroaryl, containing one tofour nitrogen atoms or one to three nitrogen atoms and one sulfur oroxygen atom;

R² represents phenyl, C₃-C₆-cycloalkyl or 5- or 6-membered heteroaryl,containing one to four nitrogen atoms or one to three nitrogen atoms andone sulfur or oxygen atom, which are unsubstituted or substituted by oneto three groups R_(a);

R³ represents hydrogen, halogen or

C₁-C₁₀-alkyl, C₁-C₁₀-alkoxy, C₁-C₁₀-alkylthio, C₁-C₁₀-alkylamino ordi-C₁-C₁₀-alkylamino; which are unsubstituted or substituted by one tothree groups R^(a);

R⁴ represents hydrogen or

C₁-C₁₀-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl; which are unsubstituted orsubstituted by one to three groups R^(a); and

X represents O, S, NR⁵ or a single bond, wherein R⁵ represents hydrogenor C₁-C₁₀-alkyl; or

R¹ and R⁵ together with the interjacent nitrogen atom form aheterocyclic ring.

Moreover, the invention relates to processes and intermediates forpreparing these compounds, to compositions comprising them and to theiruse for controlling harmful fungi.

In Vestn. Slov. Kem. Drus. (1986), 33(3), 353-66 (ISSN: 0560-3110, CAN107:39701) it is disclosed that the reaction of N-pyrimid-2-ylformamideoximes with N,N-dimethylformamide diethyl acetal yields2-(N-cyano-N-ethylamino)pyrimidines. In J. Org. Chem. 39 (9) 1256-1252(1974) N-glycosylated 2-(N-cyanoamino) pyrimidines are disclosed and inU.S. Pat. No. 4,711,959 a process for the preparation of2-(N-cyanoamino)pyrimidines is described.

It is an object of the present invention to provide fungicidal compoundshaving improved activity.

We have found that this object is achieved by the compounds defined atthe outset. Furthermore, we have found processes for their preparation,compositions comprising them and methods for controlling harmful fungiusing the compounds I.

Compounds of formula I wherein R⁴ is an optionally substituted alkyl,alkenyl or alkynyl group as defined above may be obtained by treating acompound of the formula II

in which R¹ through R³ and X are as defined in formula I; with a strongbase and an alkylation agent of formula III

R⁴—Y  III

in which R⁴ is C₁-C₆-alkyl, C₁-C₆-alkenyl or C_(l)-C₆-alkynyl; which areunsubstituted or substituted by one to three groups R^(a), and Yrepresents a nucleophilic replaceable leaving group, preferably ahalogen atom, in particular a iodine atom

Compounds of formula II are known for example from U.S. Pat. No.5,593,996, WO-A 98/46608, FR-A 2,765,875, WO-A 99/41255 or WO-A99/48893.

The reaction between the triazolopyrimidines of formula II, the strongbase and the alkylation agent of formula III is preferably carried outin the presence of an inert solvent. Suitable solvents include ethers,such as dioxane, diethyl ether and tetrahydrofuran, halogenatedhydrocarbons such as dichloromethane, amides, such as dimethylformamideor N-methylpyrrolidone and aromatic hydrocarbons, for example toluene ormixtures of these solvents. The reaction is suitably carried out at atemperature in the range from −78° C. to 100° C., the preferred reactiontemperature is from 10° C. to 80° C., particular at ambient temperature.

Suitable strong bases include metal hydrides, such as sodium hydride,potassium hydride or calcium hydride, and metal amides, such as sodiumamide, potassium amide, lithium diisopropylamide or potassiumhexamethyldisilazide, and metal alkanes such as methyllithium,n-butyllithium or tert-butyllithium.

Furthermore, the compounds of formula I wherein R⁴ is an optionallysubstituted alkyl, alkenyl or alkynyl group may be prepared by reactinga N-pyrimid-2-ylformamide oxime of formula IV

in which R¹ through R³ and X are as defined in formula I; with aN,N-dimethylformamide dialkyl acetate of formula V

in which R⁴ is is C₁-C₆-alkyl, C₁-C6-alkenyl or C₁-C₆-alkynyl; which areunsubstituted or substituted by one to three groups R^(a).

The reaction between the compounds of formula IV and the compounds offormula v can be carried out analogosly to the reaction described inVestn. Slov. Kem. Drus. (1986), 33(3), 353-66.

Compounds of formula I wherein R⁴ is hydrogen can preferably be preparedby treating sulfones of formula VI

in which R¹ through R³ and X are as defined in formula I and R⁶ isC₁-C₆-alkyl or C₁-C₆-haloalkyl; with cyanamide or with a metal salt ofcyanamide. The use of a base and/or a solvent can be advantageous.

This process is preferably carried out in the presence of an inertsolvent. Suitable solvents include aromatic hydrocarbons, such as, forexample toluene or xylene, chlorinated hydrocarbons, such as, forexample methylene chloride, chloroform, a chlorobenzene, ketones, suchas, for example acetone, methyl ethyl ketone, methyl isopropyl ketone ormethyl isobutyl ketone, nitriles, such as, for example acetonitrile orpropionitrile ethers, such as, for example diethyl ether, diisopropylether, methyl tert-butylether, dimethoxyethane, tetrahydrofuran ordioxane, amides, such as, for example, dimethylacetamide ordiethylacetamide, sulfoxides, such as, for example dimethylsulfoxide orsulfolane, or mixtures thereof.

The use of a base can be advantageous in this reaction. Suitable basesinclude alkali metal hydrides and earth alkaline metal hydrides, suchas, for example, sodium, potassium or calcium hydrides, alkali metalhydroxides and alkaline earth metal hydroxides, such as, for example,sodium, potassium or calcium hydroxides, alkali metal carbonates andalkaline earth metal carbonates, such as, for example sodium carbonate,potassium carbonate or calcium carbonate, alkali metal bicarbonates andalkaline earth metal bicarbonates, such as sodium bicarbonate, potassiumbicarbonate or calcium bicarbonate, metal amides, such as, for examplesodium amide, potassium amide, lithium diisopropylamide or potassiumhexamethyldisilazide, metal alkanes, such as for example methyl lithium,n-butyl lithium or tert-butyl lithium or aprotic amines, such as, forexample pyridine, tributylaine, N,N-dimethylbenzylamine ordiazobicycloundecene.

Various qualities of cyanamide may be employed for the process. The useof an aqueous solution of cyanamide may be preferred for practicalreasons. The use of metal salts of cyanamide, potassium cyanamide,dipotassium cyanamide or calcium cyanamide is also possible.

Dependant an the used cyanamide or salt of, cyanamide and dependant onthe base an appropriate solvent is employed.

The reaction is suitable carried out at a temperature in the range from−78° C. to reflux temperature, the preferred reaction temperature isfrom 0° C. to 150° C., particular at ambient temperature.

In general 1 to 3 equivalents, preferably 1.5 to 2.5 equivalents of baseare employed per equivalent of sulfone of the formula VI.

Generally 2 to 6 equivalents, preferably 3 to 5 equivalents of cyanamideor salt of cyanamide are employed per equivalent of the sulfone of thegeneral formula VI.

Compounds of formula I wherein R⁴ is is C₁-C₆-alkyl, C₁-C₆-alkenyl orC₁-C₆-alkynyl which are unsubstituted or substituted by one to threegroups R^(a) may be prepared by alkylation of compounds of formula Iwherein R⁴ is hydrogen with an alkylation agent of formula III.

The use of a base can be advantageous in this reaction. Suitable basesinclude alkali metal hydrides and earth alkaline metal hydrides, suchas, for example, sodium, potassium or calcium hydrides, alkali metalhydroxides and alkaline earth metal hydroxides, such as, for example,sodium, potassium or calcium hydroxides, alkali metal carbonates andalkaline earth metal carbonates, such as, for example sodium carbonate,potassium carbonate or calcium carbonate, alkali metal bicarbonates andalkaline earth metal bicarbonates, such as sodium bicarbonate, potassiumbicarbonate or calcium bicarbonate, metal amides, such as, for examplesodium amide, potassium amide, lithium diisopropylamide or potassiumhexamethyldisilazide, metal alkanes, such as for example methyl lithium,n-butyl lithium or tert-butyl lithium or aprotic amines, such as, forexample pyridine, tributylaine, N,N-dimethylbenzylamine ordiazobicycloundecene.

The alkylation is preferably carried out in the presence of an inertsolvent. Suitable solvents include aromatic hydrocarbons, such as, forexample toluene or xylene, chlorinated hydrocarbons, such as, forexample methylene chloride, chloroform, a chlorobenzene, ketones, suchas, for example acetone, methyl ethyl ketone, ethyl isopropyl ketone ormethyl isobutyl ketone, nitriles, such as, for example acetonitrile orpropionitrile ethers, such as, for example diethyl ether, diisopropylether, methyl tert-butylether, dimethoxyethane, tetrahydrofuran ordioxane, amides, such as, for example, dimethylacetamide ordiethylacetamide, sulfoxides such as, for example dimethylsulfoxide orsulfolane, or mixtures thereof.

The reaction is suitably carried out at a temperature in the range from−78° C. to reflux temperature, the preferred reaction temperature is 0°C. to 150° C., particular ambient temperature. In general 0.8 to 5equivalents, preferably 0.8 to 4.5 equivalents of the alkylation agentof the formula III are employed per equivalent of the compound offormula I.

Usually 0.8 to 3 equivalents, preferably 0.8 to 4.5 equivalents of baseare employed per equivalent of the compound of formula I.

It is also possible to prepare compounds of formula I wherein R⁴ is isC₁-C₆-alkyl, C₁-C₆-alkenyl or C₁-C6-alkynyl which are unsubstituted orsubstituted by one to three groups R^(a) by reacting a sulfone offormula VI

in which R¹ through R³ and X are as defined in formula I and R⁶ isC₁-C₆-alkyl or C₁-C₆-haloalkyl; with an alkylated cyanamide of formulaVII

wherein R⁴ is is C₁-C₆-alkyl, C₁-C₆-alkenyl or C₁-C₆-alkynyl which areunsubstituted or substituted by one to three groups R^(a). The use of abase and/or a solvent can be advantageous.

Suitable bases and solvents are such as listed at the reaction withcyanamide.

The reaction is suitable carried out at a temperature in the range offrom −78° C. to reflux temperature, the preferred reaction temperatureis from 0° C. to 150° C., particular at ambient temperature.

The reaction is in general carried out under usual pressure.

In general 1 to 3 equivalents preferably 1.5 to 2.5 equivalents of baseare employed per equivalent of the sulfone of formula VI.

Usually 2 to 6 equivalents, preferably 3 to 5 equivalents of alkylatedcyanamide of formula VII are employed per equivalents of the sulfone offormula VI.

Sulfones of the formula VI are obtained by reacting2-thiopyrimidinederivatives of the formula VIII

in which the variables are as defined in formula VI; with oxidizingagents, such as, for example m-chloroperbenzoic acid, per acetic acid,trifluoro per acetic acid, chlorine water, hypochorous acid or metalsalt solutions thereof in water or hydrogen peroxide, if appropriate inpresence of a catalyst, such as for example wolframate.

If appropriate solvents, such as for example, methylene chloride,chloroform, carbontetrachloride, 1,2-dichloroethane or chlorobenzene areused at temperatures of −20° C. to reflux.

The 2-thiopyrimidine derivatives of the formula VIII may be obtainedwhen 6-halo-2-thiopyrimidines of formula IX

in which the substituents are as before mentioned and “Hal” denoteshalogen; are reacted with a nucleophile of formula X

H—X—R¹  X

wherein R¹ and X are as defined in formula I, if appropriate in thepresence of a suitable base and if appropriate in an organic solvent.The solvents and bases employed are similar to those mentioned for thepreparation of the compounds of formula I.

6-halo-2-thiopyrimidines of formula IX are known in the art or may beprepared according following reaction sequence:

(R², R³ and R⁶ are as defined above and R is an alkyl group) Thereaction conditions are in general known in the art.

Base catalyzed reaction of dialkylmalonate with thiourea affords2-thiobarbituric acid XII which may be selectively alkylated on sulfurto yield XIII.

Halogenation, preferably chlorination or bromination, especiallychlorination, with for example phophorous oxychloride or phosphorousoxybromide in the presence of a tertiary amine base then affords thedihalo derivative XIV.

Subsequent introduction of the radical R³, if appropriate, vianucleophilic substitution affords the 6-halo-2-thiopyrimidine of formulaIX.

Sulfones of formula VI and 2-thiopyrimidine derivatives of formula VIIIare novel,

In the symbol definitions given in the formulae above, collective termswere used which generally represent the following substituents:

halogen: fluorine, chlorine, bromine and iodine;

—C₁-C₆-alkyl and the alkyl moieties of C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₁-C₆-alkylamino, di-C₁-C₆-alkylamine or

C₁-C₆-alkoxycarbonyl: saturated, straight-chain or branched hydrocarbonradicals having 1 to 6 carbon atoms, preferrably C₁-C₄-alkyl, such asmethyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl; or pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 2,2-di-methylpropyl, 1-ethylpropyl, hexyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and1-ethyl-2-methylpropyl; preferrably ethyl or methyl;

—C₁-C₆-haloalkyl and the haloalkyl moieties of C₁-C₆-haloalkoxy:straight-chain or branched alkyl groups having 1 to 6 carbon atoms (asmentioned above), where the hydrogen atoms in these groups may bepartially or fully replaced by halogen atoms as mentioned above, forexample C₁-C₂-haloalkyl, such as chloromethyl, bromomethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl,chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl;preferrably 2,2,2-trifluoroethyl or 1,1,1-trifluoroprop-2-yl;

—C₃-C₈-cycloalkyl: monocyclic, saturated hydrocarbon radicals having 3to 6 or 8 carbon ring members, for example cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, preferably 5 to 7carbon atoms, in particular cyclopentyl being optionally substituted byone or more halogen atoms, nitro, cyano, C₁-C₆-alkyl or C₁-C₆-alkoxy.

—C₂-C₄-alkenyl: unsaturated, straight-chain or branched hydrocarbonradicals having 2 to 4 carbon atoms and a double bond in any position,for example ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl,2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,1-methyl-2-propenyl and 2-methyl-2-propenyl; preferrably allyl or2-methylallyl.

—C₂-C₄-haloalkenyl and the haloalkenyl moieties of C₂-C₄-haloalkenyloxy:unsaturated, straight-chain or branched hydrocarbon radicals having 2 to4 carbon atoms and a double bond in any position (as mentioned above),where the hydrogen atoms in these groups may be partially or fullyreplaced by halogen atoms as mentioned above, in particular by fluorine,chlorine and bromine;

—C₂-C₄-alkynyl: straight-chain or branched hydrocarbon radicals having 3to 4 carbon atoms and a triple bond in any position, for exampleethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and1-methyl-2-propynyl;

—C₃-C₄-haloalkynyl and the haloalkynyl moieties of C₂-C₄-haloalkynyloxy:unsaturated, straight-chain or branched hydrocarbon radicals having 2 to4 carbon atoms and a triple bond in any position (as mentioned above),where the hydrogen atoms in these groups may be partially or fullyreplaced by halogen atoms as mentioned above, in particular by fluorine,chlorine and bromine;

5-membered heteroaryl, containing one to four nitrogen atoms or one tothree nitrogen atoms and one sulfur or oxygen atom: 5-memberedheteroaryl groups which, in addition to carbon atoms, may contain one tofour nitrogen atoms or one to three nitrogen atoms and one sulfur oroxygen atom as ring members, for example 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl,4-imidazolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl,1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl and 1,3,4-triazol-2-yl;

6-membered heteroaryl, containing one to four nitrogen atoms: 6-memberedheteroaryl groups which, in addition to carbon atoms, may contain one tothree or one to four nitrogen atoms as ring members, for example2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl and 1,2,4-triazin-3-yl; preferred hetaryl moietiesare pyridyl, pyrimidyl, pyrazolyl or thienyl.

5- or 6-membered heterocyclyl, containing one to four nitrogen atoms orone to three nitrogen atoms and one sulfur or oxygen atom, for example2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl,3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl,4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl,4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl,4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl,5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 1,2,4-oxadiazolidin-3-yl,1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl,1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl,1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl,1,3,4-triazolidin-2-yl, 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl,2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl,2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl,2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl,2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl,2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl,2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl,2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl,2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl,2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl,2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl,2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl,2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl,3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl,3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl,4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl,4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl,2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl,3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl,2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl,3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl,4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl,1,3,5-hexahydro-triazin-2-yl and 1,2,4-hexahydrotriazin-3-yl; preferredheterocyclyl groups are pyrrolidinyl, pyrazolidinyl, piperidinyl,piperazinyl or morpholin-4-yl.

The particularly preferred embodiments of the intermediates with respectto the variables correspond to those of the radicals R¹, R², R³ and R⁴of formula I.

With respect to their intended use, preference is given to pyrimidinesof formula I having the following substituents, where the preference isvalid in each case on its own or in combination:

Compounds of formula I are preferred wherein R¹ denotes C₃-C₁₀-alkyl,C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₁-C₁₀-haloalkyl orphenyl being optionally substituted by one to three halogen atoms orC₁-C₁₀-alkyl or C₁-C₁₀-alkoxy.

Furthermore, particular preference is given to compounds I in which R¹is C₁-C₁₀haloalkyl, preferably polyfluorinated alkyl, in particular2,2,2-trifluoroethyl, 2-(1,1,1-trifluoropropyl) or2-(1,1,1-trifluorobutyl).

Likewise, particular preference is given to compounds I in which R¹denotes optionally substituted C₃-C₈-cycloalkyl, preferably cyclopentylor cyclohexyl.

Moreover, particular preference is given to compounds I in which R²represents phenyl being substituted by 2 or 3 substituents. Mostpreferred at least one of these substituents is attached in the2-position with respect to the point of attachment to the pyrimidinemoiety. Such substituents preferably include halogen or alkoxy.

Furthermore, particular preference is given to compounds I in which R²represents a phenyl group of formula

wherein L¹ through L⁴ each independently represent hydrogen, fluorine,chlorine or methoxy, in particular L¹ represents fluorine or chlorine,L² and L⁴ each independently represent hydrogen, fluorine or chlorine,and L³ represents hydrogen, fluorine, chlorine or methoxy.

Particular preference is given to compounds of formula I in which R³ ischlorine.

Besides, particular preference is given to compounds I in which R⁴represents hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl; orphenyl-C₁-C₄-alkyl, wherein the phenyl ring may be substituted by one ortwo halogen atoms.

Likewise, particular preference is given to compounds I in which R⁴ ishydrogen, C₁-C₆-alkyl or benzyl, especially C₁-C₆-alkyl.

Particular preference is given to compounds I in which X is NR⁵ and R⁵is hydrogen, C₁-C₁₀-alkyl or C₁-C₁₀-haloalkyl, in particular hydrogen.

Besides, particular preference is given to compounds I in which R⁵represents C₁-C₆-alkyl, especially hydrogen or methyl.

Particular preference is also given to compounds I in which X representNR⁵ and R¹ together with the interjacent nitrogen atom form anoptionally substituted heterocyclic ring, preferably an optionallysubstituted 3- to 7-membered heterocyclic ring, in particular apyrrolidine, piperidine, tetrahydropyridine, in particular1,2,3,6-tetrahydropyridine or azepane ring which is optionallysubstituted by one or more C₁-C₁₀-alkyl groups.

Most preferred are the compounds of formula IA

in which R¹ to R⁵ have the meaning given in formula I, L¹ is F or Cl, L²and L⁴ each independently are H, F or Cl, and L³ is H, F, Cl or OCE₃.

Likewise, most preferred are the compounds wherein R³ is chlorine, X isNH, R⁴ is C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, especiallyC₁-C₆-alkyl, R² represents phenyl optionally substituted by one or morefluorine and/or chlorine atoms and/or methoxy groups.

Particularly preferred are following compounds of formula IA:

R¹ R⁵ R³ R⁴ L¹ L² L³ L⁴ CH(CH₃)CF₃ H Cl CH₃ F H F F CH(CH₃)CF₃ H Cl(CH₂)₃CH₃ F H F F CH(CH₃)₂ H Cl CH₃ F H F F c—C₃H₅ H Cl CH₃ F F H Fazepan-1-yl H Cl CH₃ H F H F (CH₂)₂CH(CH₃)(CH₂)₂ Cl CH₃ F H H ClCH(CH₃)CH₂CH₃ H Cl CH₃ F H H Cl (CH₂)₂CH(CH₃)(CH₂)₂ Cl CH₃ F H F FCH(CH₃)CF₃ H Cl CH₃ F H F F

Included in the scope of the present Invention are (R) and (S) isomersof compounds of general formula I having a chiral center and theracemates thereof, and salts, N-Oxides and acid addition compounds.

The compounds according to formula I are superior through their valuablefungicidal properties, in particular their enhanced systemicity. Forexample, they can be used in agriculture or related fields for thecontrol of phytopathogenic fungi such as Alternaria solani, Botrytiscinerea, Cercospora beticola, Cladosporium herbarum, Corticium rolfsi,Erysiphe graminis, Helminthosporium tritici repentis, Lepfosphaerianodorum, Micronectriella nivalis, Monilinia fructigena, Mycosphaerellaligulicola, Mycosphaerella pinodes, Rhizotonia solani, Sclerotiniasclerotiorum, Uncinula necator and Venturia inaequalis, in particularPyricularia oryzae, Rhizoctonia solani and Venturia inaequalis. Thecompounds of formula I according to the invention possess a highfungicidal activity within a wide concentration range.

Due to excellent activity, the compounds of formula I may be used incultivation of all plants where infection by phytopathogenic fungi isnot desired, e.g. cereals, solanaceous crops, vegetables, legumes,appies, vine.

The Invention further provides a fungicidal composition which comprisesan active ingredient, which is at least one compound of formula I asdefined above, and one or more carriers. A method of making such acomposition is also provided which comprises bringing a compound offormula I as defined above into association with the carrier(s). Such acomposition may contain a single active ingredient or a mixture ofseveral active ingredients of the present Invention. It is alsoenvisaged that different isomers or mixtures of isomers may havedifferent levels or spectra of activity and thus compositions maycomprise individual isomers or mixtures of isomers.

A composition according to the Invention preferably contains from 0.5%to 95% by weight (w/w) of active ingredient.

A carrier in a composition according to the Invention is any materialwith which the active ingredient is formulated to facilitate applicationto the locus to be treated, which may for example be a plant, seed,soil, or water in which a plant grows, or to facilitate storage,transport or handling. A carrier may be a solid or a liquid, includingmaterial which is normally a gas but which has been compressed to form aliquid.

The compositions may be manufactured into e.g. emulsion concentrates,solutions, oil in water emulsions, wettable powders, soluble powders,suspension concentrates, dusts, granules, water dispersible granules,micro-capsules, gels, tablets and other formulation types by wellestablished procedures. These procedures include intensive mixing and/ormilling of the active ingredients with other substances, such asfillers, solvents, solid carriers, surface active compounds(surfactants), and optionally solid and/or liquid auxiliaries and/oradjuvants. The form of application such as spraying, atomizing,dispersing or pouring may be Chosen like the compositions according tothe desired objectives and the given circumstances.

Solvents may be aromatic hydrocarbons, e.g. Solvess® 200, substitutednaphthalenes, phthalic acid esters, such as dibutyl or dioctylphthalate, aliphatic hydrocarbons, e.g. cyclohexane or Paraffins,alcohols and glycols as well as their ethers and esters, e.g. ethanol,ethyleneglycol mono- and dimethyl ether, ketones such as cyclohexanone,strongly polar solvents such as N-methyl-2-pyrrolidone, orγ-butyrolactone, higher alkyl pyrrolidones, e.g. n-octylpyrrolidone orcyclohexylpyrrolidone, epoxidized plant oil esters, e.g. methylatedcoconut or soybean oil ester and water. Mixtures of different liquidsare often suitable.

Solid carriers, which may be used for dusts, wettable powders, waterdispersible granules, or granules, may be mineral fillers, such ascalcite, talc, kaolin, montmorillonite or attapulgite. The physicalproperties may be improved by addition of highly dispersed silica gel orPolymers. Carriers for granules may be porous material, e.g. pumice,kaolin, sepiolite, bentonite; non-sorptive carriers may be calcite orsand. Additionally, a multitude of pregranulated inorganic or organicmaterials may be used, such as dolomite or crushed plant residues.

Pesticidal compositions are often formulated and transported in aconcentrated form which is subsequently diluted by the user beforeapplication. The presence of small amounts of a carrier which is asurfactant facilitates this process of dilution. Thus, preferably atleast one carrier in a composition according to the Invention is asurfactant. For example, the composition may contain at two or morecarriers, at least one of which is a surfactant.

Surfactants may be nonionic, anionic, cationic or zwitterionicsubstances with good dispersing, emulsifying and wetting propertiesdepending an the nature of the compound according to general formula Ito be formulated. Surfactants may also mean mixtures of individualsurfactants

The compositions of the Invention may for example be formulated aswettable powders, water dispersible granules, dusts, granules, tablets,solutions, emulsifiable concentrates, emulsions, suspension concentratesand aerosols. Wettable powders usually contain 5 to 90% w/w of activeingredient and usually contain in addition to solid inert carrier, 3 to10% w/w of dispersing and wetting agents and, where necessary, 0 to 10%w/w of stabilizer(s) and/or other additives such as penetrants orstikkers. Dusts are usually formulated as a dust concentrate having asimilar composition to that of a wettable powder but without adispersant, and may be diluted in the field with further solid carrierto give a composition usually containing 0.5 to 10% w/w of activeingredient. Water dispersible granules and granules are usually preparedto have a size between 0.15 mm and 2.0 mm and may be manufactured by avariety of techniques. Generally, these types of granules will contain0.5 to 90% w/w active ingredient and 0 to 20% w/w of additives such asstabilizer, surfactants, slow release modifiers and binding agents. Theso-called “dry flowables” consist of relatively small granules having arelatively high concentration of active ingredient. Emulsifiableconcentrates usually contain, in addition to a solvent or a mixture ofsolvents, 1 to 80% w/v active ingredient, 2 to 20% w/v emulsifiers and 0to 20% w/v of other additives such as stabilizers, penetrants andcorrosion inhibitors. Suspension concentrates are usually milled so asto obtain a stable, nonsedimenting flowable product and usually contain5 to 75% w/v active ingredient, 0.5 to 15% w/v of dispersing agents, 0.1to 10% w/v of suspending agents such as protective colloids andthixotropic agents, 0 to 10% W/v of other additives such as defoamers,corrosion inhibitors, stabilizers, penetrants and stickers, and water oran organic liquid in which the active ingredient is substantiallyinsoluble; certain organic solids or inorganic salis may be presentdissolved in the formulation to assist in preventing sedimentation andcrystalization or as antifreeze agents for water. Aqueous dispersionsand emulsions, for example compositions obtained by diluting theformulated product according to the Invention with water, also liewithin the scope of the invention.

Of particular interest in enhancing the duration of the protectiveactivity of the compounds of this Invention is the use of a carrierwhich will provide slow release of the pesticidal compounds into theenvironment of a plant which is to be protected.

The biological activity of the active ingredient can also be increasedby including an adjuvant in the spray dilution. An adjuvant is definedhere as a substance which can increase the biological actively of anactive ingredient but is not itself significantly biologically active.The adjuvant can Bither be included in the formulation as a coformulantor carrier, or can be added to the spray tank together with theformulation containing the active ingredient.

As a commodity the compositions may preferably be in a concentrated formwhereas the end user generally employs diluted compositions. Thecompositions may be diluted to a concentration down to 0.001% of activeingredient. The doses usually are in the range from 0.01 to 10 kga.i./ha.

Examples of formulations according to the Invention are:

Emulsion Concentrate (EC) Active Ingredient Compound of Example 5 30%(w/v) Emulsifier(s) Atlox ® 4856 B/Atlox ® 4858 B¹⁾ 5% (w/v) (mixturecontaining calcium alkyl aryl sulfonate, fatty alcohol ethoxylates andlight aromatics/mixture containing calcium alkyl aryl sulfonate, fattyalcohol ethoxylates and light aromatics) Solvent Shellsol ® A²⁾ to 1000ml (mixture of C₉-C₁₀-aromatic hydrocarbons) Suspension Concentrate (SC)Active Ingredient Compound of Example 5 50% (w/v) Dispersing agentSoprophor ® FL³⁾ 3% (w/v) (polyoxyethylene polyaryl phenyl etherphosphate amine satt) Antifoaming agent Rhodorsil ® 422³⁾ 0.2 (w/v)(nonionic aqueous emulsion of polydimethylsiloxanes) Structure agentKelzan ® S⁴⁾ 0.2 (w/v) (Xanthan gum) Antifreezing agent Propylene glycol5% (w/v) Biocidal agent Proxel ®⁵⁾ 0.1 (w/v) (aqueous dipropylene glycolsolution containing 20% 1,2-beniso- thiazolin-3-one) Water to 1000 mlWettable Powder (WP) Active Ingredient Compound of Example 7 60% (w/w)Wetting agent Atlox ® 4995¹⁾ 2% (w/w) (polyoxyethylene alkyl ether)Dispersing agent Witcosperse ® D-60⁶⁾ 3% (w/w) (mixture of sodium saltsof condensed naphthalene suffonic acid and alkylarylpolyoxy acetatesCarrier/Filter Kaolin 35% (w/w) Water Dispersible Granules (WG) ActiveIngredient Compound of Example 7 50% (w/w) Dispersing/ Witcosperse ®D-450⁶⁾ 8% (w/w) Binding agent (mixture of sodium salts of condensednaphthalene sulfonic acid and alkyl sulfonates) Wetting agent Morwet ®EFW⁶⁾ 2% (w/w) (formaldehyde condensation product) Antifoaming agentRhodorsil ® EP 6703³⁾ 1% (w/w) (encapsulated silicone) DisintegrantAgrimer ® ATF') 2% (w/w) (cross-linked homopolymer of N-vinyl-2pyrrolidone) Carrier 1 Filter Kaolin 35% (w/w) ¹⁾commerciallyavailable from ICI Surfactants ²⁾commercially available from DeutscheShell AG ³⁾commercially available from Rhöne-Poulenc ⁴⁾commerciallyavailable from Kelco Co. ⁵⁾commercially available from Zeneca⁶⁾commercially available from Witco ⁷⁾commercially available fromInternational Speciality Products

The compositions of this invention can be applied to the plants or theirenvironment simultaneous with or in succession with other activesubstances. These other active substances can be Bither fertilisers,agents which donate trace elements or other preparations which influenceplant growth. However, they can also be selective herbicides,insecticides, fungicides, bactericides, nematicides, algicides,molluscicides, rodenticides, virucides, compounds inducing resistanceinto plants, biological control agents such as viruses, bacteria,nematodes, fungi and other microorganisms croorganisms, repellents ofbirds and animals, and plant growth regulators, or mixtures of severalof these preparations, if appropriate together with other carriersubstances conventionally used in the art of formulation, surfactants orother additives which promote application.

Furthermore, the other pesticide can have a synergistic effect anthepesticidal activity of the compound of formula I. The other fungicidalcompound can be, for example, one which is also capable of combatingdiseases of cereals (e.g. wheat) such as those caused by Erysiphe,Puccinia, Septoria, Gibberella and Helminthosporium spp., seed and soilBorne diseases and downy and powdery mildews an eines, early and lateblight an solanaceous crops, and powdery mildew and scab an apples etc.These mixtures of fungicides can have a broader spectrum of activitythan the compound of general formula I alone. Furthermore, the otherfungicide can have a synergistic effect an the fungicidal activities ofthe compound of formula I.

Examples of the other fungicidal compounds are anilazine, azoxystrobin,benalaxyl, benomyl, binapacryl, bitertanol, blasticidin S, Bordeauxmixture, bromuconazole, bupirimate, captafol, captan, carbendazim,carboxin, carpropamid, chlorbenzthiazon, chlorothalonil, chlozolinate,copper-containing compounds such as copper oxychloride, and coppersulfate, cycloheximide, cymoxanil, cypofuram, cyproconazole, cyprodinil,dichlofluanid, dichlone, dichloran, diclobutrazol, diclocymet,diclomezine, diethofencarb, difenoconazole, diflumetorim, dimethirimol,dimethomorph, diniconazole, dinocap, ditalimfos, dithianon, dodemorph,dodine, edifenphos, epoxiconazole, etaconazole, ethirimol, etridiazole,famoxadone, fenapanil, fenamidone, fenarimol, fenbuconazole, fenfuram,fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fentin,fentin acetate, fentin hydroxide, ferimzone, fluazinam, fludioxonil,flumetover, fluquinconazole, flusilazole, flusulfamide, flutolanil,flutriafol, folpet, fosetylaluminium, fuberidazole, furalaxyl,furametpyr, guazatine, hexaconazole, IKF-916, imazalil, iminoctadine,ipconazole, iprodione, isoprothiolane, iprovalicarb, kasugamycin,KH-7281, kitazin P, kresoximmethyl, mancozeb, maneb, mepanipyrim,mepronil, metalaxyl, metconazole, methfuroxam, MON 65500, myclobutanil,neoasozin, nicket dimethyldithiocarbamate, nitrothalisopropyl, nuarimol,ofurace, organo mercury compounds, oxadixyl, oxycarboxin, penconazole,pencycuron, phenazineoxide, phthalide, polyoxin D, polgram, probenazole,prochloraz, procymidione, propamocarb, propiconazole, propineb,pyraclostrobin, pyrazophos, pyrifenox, pyrimethanil, pyroguilon,pyroxyfur, quinomethionate, quinoxyfen, quintozene, spiroxamine,SSF-126, SSF-129, streptomycin, sulfur, tebuconazole, tecloftalame,tecnazene, tetraconazole, thiabendazole, thifluzamide,thiophanate-methyl, thiram, tolclofosmethyl, tolylfluanid, triadimefon,triadimenol, triazbutil, triazoxide, tricyclazole, tridemorph,trifloxystrobin, triflumizole, triforine, triticonazole, validamycin A,vinclozolin, XRD-563, zarilamid, zineb, ziram.

In addition, the co-formulations according to the Invention mag containat least one compound of formula I and any of the following classes ofbiological control agents such as viruses, bacteria, nematodes, fungi,and other microorganisms which are suitable to control insects, weeds orplant diseases or to induce holt resistance in the plants. Examples ofsuch biological control agents are: Bacillus thuringiensis, Verticilliumlecanu, Autographica californica NPV, Beauvaria bassiana, Ampelomycesquisqualis, Bacilis subtilis, Pseudomonas chlororaphis, Pseudomonasfluorescens, Steptomyces griseoviridis and Trichoderma harzianum.

Moreover, the co-formulations according to the Invention mag contain atleast one compound of formula I and a chemical agent that induces thesystemic acquired resistance in plants such as for example isonicotinicacid or derivatives thereof,2,2-dichloro-3,3-dimethylcyclopropanecarboxylic acid or BION.

The compounds of formula I can be mixed with soil, peat or other rootingmedia for the protection of the plants against seed-Borne, soilborne orfoliar fungal diseases.

The Invention still further provides the use as a fungicide of acompound of the formula I as defined above or a composition as definedabove, and a method for combating fungus at a locus, which comprisestreating the locus, which may be for example plants subject to orsubjected to fungal attack, seeds of such plants or the medium in whichsuch plants are growing or are to be grown, with such a compound orcomposition.

The present Invention is of wide applicability in the protection of cropand ornamental plants against fungal attack. Typical crops which may beprotected include eines, grain crops such as wheat and barley, rice,sugar Beet, top fruit, peanuts, potatoes, vegetables and tomatoes. Theduration of the protection is normally dependent an the individualcompound selected, and also a variety of external factors, such asclimate, whose Impact is normally mitigated by the use of a suitableformulation.

Synthesis Examples

With due modification of the starting compounds, the protocols shown inthe synthesis examples below were used for obtaining further compoundsI. The resulting compounds, together with physical data, are listed inthe Tables which follow.

EXAMPLE 1

Preparation of2-(N-cyano-N-methylamino)-4-chloro-5-(2,4,6-trifluorophenyl)-6-(1,1,1-trifluoroprop-2-ylamino)-pyrimidine

A mixture of5-chloro-6-(2,4,6-trifluorophenyl)-7-(1,1,1-trifluoroprop-2-ylamino)-triazolo[1.5a]pyrimidine(2.5 g, 6.3 imol, prepared according to WO-A 98/46608);dimethylformamide (15 ml), sodium hydride (0.25 g, 60%) and methyliodideis stirred at ambient temperature for 45 minutes. The reaction mixtureis poured into water (400 ml) and extracted with diethylether twice (300ml). The organic Phase is separated, dried with anhydrous sodiumsulphate and filtered. The filtrate is evaporated under reduced Pressureand purified by flash chromatography to yield 0.2 g of the product as acolorless oil.

EXAMPLE 2-20

TABLE I (synthesized analogously to Ex. 1)

melting point Ex. R¹ R⁵ R⁴ L¹ L² L³ L⁴ (° C.) 2 1,1,1-trifluoro- H butylF H F F 168-172 prop-2-yl 3 iso-propyl H methyl F H F F 130 4cyclopentyl H methyl F F H F 140 5 —(CH₂)₂—CH(CH₃)—(CH₂)₂— methyl F H HCl oil 6 2-butyl H methyl F H H Cl oil 7 —(CH₂)₂—CH(CH₃)—(CH₂)₂— methylF H F F 100 8 1,1,1-trifluoro methyl methyl F H F F  86 prop-2-yl 9but-2-yl ethyl methyl F H F F 10 norborn-2-yl H methyl F H F F 11—(CH₂)₂—CH(CH₃)—(CH₂)₂— methyl F H H Cl 12 cyclopentyl H methyl F H F F13 iso-propyl H methyl F H H Cl 14 ethyl ethyl methyl F H F F 152,2,2-trifluoro- H methyl F H F F ethyl 16 1,1,1trifluoro- H ethyl F HCl prop-2-yl 17 2-butyl H methyl F H H Cl oil 18 norborn-2-yl H methyl FH H Cl 19 1,1,1-trifluoro- H methyl F H OCH₃ F prop-2-yl 20 methallylethyl methyl F H F F 21 2,2,2-trifluoro- H allyl F H H Cl 177 ethyl 221,1,1-trifluoro- H n-pro- F H F F 168-172 prop-2-yl pyl 23 —(CH₂)₇—methyl H F H F oil 24 iso-propyl methyl methyl F H H Cl oil 251,1,1-trifluoro- H methyl F H F F oil prop-2-yl

EXAMPLE 26

Preparation of2-(N-cyano-N-methylamino)-4-chloro-5-(2,4,6-trifluorophenyl)-6-cyclohexylpyrimidine

A mixture of5-chloro-6-(2,4,6-trifluorophenyl)-7-cyclohexyltriazolo[1.5a]pyrimidine(2.5 g, 6.3 mmol, prepared according to WO-A 99/41255),dimethylformamide (15 ml), sodium hydride (0.25 g, 60%) and methyliodideis stirred at ambient temperature for 45 minutes. The reaction mixtureis poured into water (400 ml) and extracted with diethylether twice (300ml). The organic phase is separated, dried with anhydrous sodiumsulphate and filtered. The filtrate is evaporated under reduced pressureand purified by flash chromatography to yield 0.2 g of the product as acolorless oil.

EXAMPLE 27-39

TABLE II (synthesized analogously to Ex. 26)

melting point Ex. R¹ L¹ L³ L⁴ (° C.) 27 n-heptyl F F F 28 cyclopentyl FF F 29 cyclohexyl F F F 30 4-methylcyclohexyl F F F 31 2-methylpropyl FF F 32 n-heptyl F H Cl 33 cyclopentyl F H Cl 34 cyclohexyl F H Cl 35n-hexyl F H Cl 36 4-methylcyclohecyl F N Cl 37 2-methylpropyl F H Cl 384-fluorocyclohexyl F F F 39 4-fluorocyclohexyl F OCH₃ F

EXAMPLE 40

Preparation of4-chloro-2-(N-cyanoamino)-6-[(4-methyl)-piperidin-1-yl]-5-phenylpyrimidine

To a solution of4-chloro-6-[(4-methyl)-piperidin-1-yl]-2-methylsulfony-5-phenyl-pyrimidine(1.0 g, 2.7 mmol) in dimethylformamide (8 ml) at room temperature wasadded potassium carbonate (0.76 g, 5.47 mmol). After the reactionmixture had been stirred at room temperature for 17.5 hours the reactionmixture was then diluted with water (70 mI) and the resulting cloudysolution acidified to pH 1 by the addition of concentrated hydrochloricacid (4 ml). The resulting white suspension was then stirred at roomtemperature for 2 hours. The suspension was then filtered, washed withwater followed by hexane and dried in vacuo overnight. The crude productwas recrystaliized from methylene chloride/hexane to afford 0.71 g (79%yield) of the title compound as a white crystalline solid (meltingpoint: 219-220° C. (dec)).

EXAMPLE 41

Preparation of4-chloro-2-(N-cyano-N-methylamino)-6-[(4-methyl)-piperidin-1-yl]-5-phenylpyrimidine

To a solution of4-chloro-2-(N-cyanoamino)-6-[(4-methyl)-piperidin-1-yl]-5-phenylpyrimidine(0.1 g, 0.305 mmol) in dimethylformamide (4 ml) at room temperature wasadded water (2 ml) followed by potassium carbonate (0.084 g, 0.61 mmol)and the resulting suspension was warmed gently to afford a clearsolution. To the cooled solution was then added methyl iodide (0.076 ml,1.22 mmol) and the reaction mixture stirred at room temperature for 2.5hours. The reaction was then quenched by the addition of saturatedaqueous ammonium chloride solution (40 ml). After adding ethyl acetate(40 ml) the biphasic mixture was stirred for 5 minutes. The organicphase was then separated, washed with saturated brine (50 ml), driedover magnesium sulfate and concentrated in vacuo to afford a yellowsyrup. The crude product was chromatographed an silica gel eluting with90:10 v/v hexane: ethyl acetate to afford 0.09 g (87% yield) of thetitle compound as a colorless syrup.

EXAMPLE 42

Preparation of2-(N-benzyl-N-cyano)-4-chloro-6-[(4-methyl)-piperidin-1-yl]-5-phenylpyrimidine

To a solution of4-chloro-2-(N-cyanoamino)-6-[(4-methyl)-piperidin-1-yl]-5-phenyl-pyrimidine(0.37 g, 1.13 mmol) in dimethylformamide (10 ml) at room temperature wasadded water (3 ml) and potassium carbonate (0.19 g, 1.35 mmol). To theresulting milky suspension benzyl bromide (0.16 ml, 1.35 mmol) was addedand stirred at room temperature for 18.75 hours before being quenched bythe addition of a saturated aqueous ammonium chloride solution (40 ml).The mixture was then partitioned between ethyl acetate (75 ml) and water(75 ml), dried over magnesium sulfate and concentrated in vacuo toafford a yellow syrup. The crude product was chromatographed an silicagel eluting with 90:10 v/v hexane: ethyl acetate to afford 0.47 g (100%yield) of the title compound as a white crystalline solid (melting point98-100° C.).

EXAMPLE 43

Alternative preparation of4-chloro-2-(N-cyano-N-methylamino)-6-[(4methyl)-piperidin-1-yl]-5-phenylpyrimidine

To a solution of4-chloro-6-[(4-methyl)-piperidin-1-yl]-2-methylsulfonyl-5-phenyl-pyrimidine(0.5 g, 1.37 mmol) in dimethylformamide (6 ml) was added potassiumcarbonate (0.38 g, 2.73 mmol) followed by methyl cyanamide (0.31 g, 5.47mmol). After stirring the reaction mixture at room temperature for 19hours the reaction mixture was diluted with water (75 ml), and extractedwith ethyl acetate (75 ml). The organic phase was washed with water (75ml), followed by saturated brine (75 ml), dried over magnesium sulfateand concentrated in vacuo to afford a yellow syrup. The crude productwas chromatographed an silica gel eluting with 90:10 v/v hexane: ethylacetate to afford 0.39 g (84% yield) of the title compound as acolorless syrup.

EXAMPLE 44

Preparation of the starting material4-chloro-6-[(4-methyl)-piperidin-1-yl]-2-methylsulfonyl-5-phenylpyrimidine

Step a: 5-Phenyl-2-methylthio-4,6(1H,5H)-pyrimidinedione

60.0 g (208 mmol) of ethyl 2-phenylmalonate and 19.0 g (249 mmol) ofthiourea were heated at 150° C. for 2.5 hours in 77 g (416 mmol) oftri-n-butylamine. The resultant ethanol was for the most part distilledoff. After the reaction solution had cooled, 180 ml of an aqueoussolution of 24.9 g (623 mmol) of NaOH were added to it. After adding 50ml of cyclohexane and stirring for about 30 min the aqueous phase wasseparated off, treated with 35.4 g (142 mmol) of methyl iodide andstirred at approximately 20 to 25° C. for about 16 h. Afteracidification with dilute HCl solution and stirring for about 30 min theprecipitate was filtered off. After washing with water and drying, 16.7g of the compound in the title (28% of theoretical) were obtained in theform of white crystals.

Step b: 4,6-Dichloro-5-phenyl-2-methylthiopyrimidine

A solution of 48.8 g (170 mmol) of the product from step A in 200 ml ofphosphoryl chloride to which 3 ml of dimethylformamide (DMF) had beenadded was refluxed for 40 hours. After distilling off most of thephosphoryl chloride and diluting the residue with ethyl acetate, waterwas added while stirring at 15 to 20° C. After phase separation, theorganic phase was washed with water and dilute NaHCO3 solution, thendried and freed of solvent. 37.5 g of the compound in the title (68% oftheoretical) were obtained in the form of an oil which was employed instep C without further purification.

Step c:6-Chloro-5-phenyl-4-[(4-methyl)piperidin-1-yl]-2-methylthiopyrimidine

A solution of 37.5 g (324 mmol) of the product from step B in 150 ml ofanhydrous dichloromethane was treated with 24 g (406 mmol) ofisopropylamine and stirred for five hours at about 20 to 25° C. Thesolvent was then distilled off, the residue taken up in ethyl acetateand washed with dilute HCl, water and dilute NaHCO₃ solution, then driedand freed of solvent. After chromatographing the residue on silica gel(cyclohexane/methyl tert-butyl ether 100:1 to 19:1) 13.4 g of the titlecompound (33% of theoretical) were obtained in the form of colorlesscrystals which were employed in the next stage without furtherpurification.

Step d: Preparation of6-chloro-4-[(4-methyl)-piperidin-1-yl]-2-methyl-sulfonyl-5phenylpyrimidine

A solution of 4-chloro-6-[(4-methyl)-piperidin-1-yl]-2-methyl-thio-5phenylpyrimidine (17.19 g, 51.5 mmol) in methylene chloride (350 ml) wascooled to 0° C. After adding 70% in chloroperbenzoic acid (25.4 g, 103mmol) the reaction mixture was stirred at 0° C. for 1 hour and at roomtemperature for 1.5 hours. The reaction mixture was then concentrated invacuo to a small volume, diluted with ethyl acetate (400 ml), washedwith 5% aqueous solution of sodium carbonate (3×300 ml) and saturatedbrine (300 ml), dried over magnesium sulfate and concentrated in vacuoto afford a white solid which was then recrystallized from ethylacetate/hexane to afford 14.68 g (78% yield) of the title compound as anoff-white crystalline solid (melting point: 160-162° C.)

EXAMPLE 45

Preparation of the intermediate4-chloro-6-(N-cyclopentyl)amino-5-(2-fluorophenyl)-2-methylthiopyrimidine

Step a: Preparation of 5-(2-fluorophenyl)-2-thiobarbituric acid

To absolute ethanol (200 ml), sodium (3.62 g, 157 mmol) was added atroom temperature under nitrogen atmosphere. The reaction mixture wasstirred until all the sodium had reacted A solution ofdiethyl-(2-fluorophenyl)malonate (20 g, 78.7 mmol) in absolute ethanol(50 ml) was then added followed by thiourea (8.38 g, 110 mmol). Thereaction mixture was then refluxed under nitrogen atmosphere for 17hours. The cooled reaction mixture was then poured into water (800 ml),the reswiting mixture stirred for 15 minutes and extracted with diethylether (500 ml) The organic phase was extracted with brine (150 ml, ⅓saturated) and the aqueous layers combined. Now concentratedhydrochloric acid (14 ml) was added to the aqueous phase and theresulting white suspension was stirred gently for 1 hour. The suspensionwas filtered and the resulting solid washed with water, followed bydiethyl ether and dried in vacuo for approximately 12 hours to afford8.59 g (46% yield) of the title compound as a white solid (meltingpoint: >240° C.).

Step b: Preparation of4,6-dihydroxy-5-(2-fluorophenyl)-2-methylthiopyrimidine

To a mixture of 5-(2-fluorophenyl)-2-thiobarbituric acid (8.20 g, 34.3mmol) and a 2.0M aqueous solution of sodium hydroxide (68.8 ml, 13.8mmol) was added dropwise over 30 minutes dimethyl sulfate (4.348, 34.4mmol) at room temperature with stirring The reaction mixture was stirredthen for an additional 24 hours at room temperature. After washing withethyl acetate (2×100 ml) the aqueous phase was acidified to pH 1 byadding concentrated hydrochloric acid (8 ml). The resulting whitesuspension was stirred for 30 minutes, filtered and the resulting whitesolid washed with water followed by hexane and dried under vacuum toafford 7.11 g of a white solid. Ethyl acetate (100 ml) was added to thecrude product and the resulting suspension refluxed while stirring for15 minutes. The cooled suspension was then filtered and dried to afford5.41 g (615 yield) of the title compound as a white solid (m. p. >240°C.).

Step c: Preparation of4,6-dichloro-5-(2-fluorophenyl)-2-methylthiopyrimidine

To a suspension of4,6-dihydroxy-5-(2-fluorophenyl)-2-methylthiopyrimidine (0.75 g, 2.97mmol) in phosphorous oxychloride (7.5 ml, 80.5 mmol) was addedtri-n-propylamine (1.24 ml, 6.54 mmol) at room temperature undernitrogen atmosphere. After refluxing the reaction mixture for 18 hoursand cooling to room temperature the reaction mixture was concentrated invacuo and the resulting dark brown residue was dissolved in a minimumamount of acetonitrile and added to water (75 ml) under stirring. Ethylacetate (75 ml) was then added and the resulting biphasic mixturestirred vigorously for one hour. The organic phase was separated, washedwith 2M aqueous hydrochloric acid (75 ml), saturated aqueous sodiumbicarbonate solution (2×75 ml) and saturated brine (75 ml). After dryingover magnesium suifate the organic Phase was concentrated in vacuo toafford a light brown oil. The crude product was chromatographed onsilica gel eluting with 98:2 v/v hexane: ethyl acetate to afford 0.74 g(86% yield) of the title compound as colorless crystals.

Step d: Preparation of4-chloro-6-(N-cyclopentyl)amino-5-(2-fluorophenyl)-2-methylthiopyrimidine

To a solution of 4,6-dichloro-5-(2-fluorophenyl)-2-methylthiopyrimidine(0.74 g, 256 mmol) in methylene chloride (1 ml) at room temperatureunder nitrogen atmosphere was added cyclopentyl-amine (1.01 ml, 10.24mmol) and the reaction mixture was stirred at room temperature for 15hours. The reaction mixture was then diluted with 1:1 v/v diethyl etherethyl acetate (75 ml), washed with 1M aqueous hydrochloric acid (2×75ml), saturated aqueous sodium bicarbonate solution (75 ml) and saturatedbrine (75 ml), dried over magnesium sulfate and concentrated in vacuo toafford a colorless syrup. The crude product was chromatographed onsilica gel eluting with 95:5 v/v hexane: ethyl acetate to afford 0.87 g(100% yield) of the title compound as a white crystalline solid (meltingpoint: 81-83° C.).

EXAMPLE 46

Preparation of the intermediate4,6-dichloro-5-(2-chloro-6-fluorophenyl)-2-methylthiopyrimidine

Step a: Preparation of4,6-dihydroxy-5-(2-chloro-5-fluorophenyl)-2-methylthiopyrimidine

A mixture of diethyl(2-chloro-6-fluorophenyl)malonate (12.01 g, 41.6mmol), thiourea (3.8 g, 49.92 mmol) and tributylamine (19.82 ml, 83.2mmol) was stirred at 150° C. under nitrogen atmosphere for 3 hours Thecooled reaction mixture was then partitioned between ethyl acetate (84ml) and 2.0M sodium hydroxide solution (83.2 ml, 106 mmol) with vigorousstirring for 15 minutes. The aqueous phase was separated, dimethylsulfate (5.258, 41.6 mmol) added and the mixture stirred forapproximately 12 hours at room temperature, Additional 5.0 sodiumhyroxide solution (33.4ml, 166 mmol) and dimetylsulfate (2.63 g, 20.8mmol) were added and the mixture stirred for further 2 hours. Theresulting suspension was then filtered, the filtrate acidified to pH 1by the addition of concentrated hydrochloric acid and stirred for 30minutes. The resulting suspension was then filtered and the resultingwhite solid washed with water followed by hexane and dried under vacuumapproximately 12 hours to afford 2.57 g (22% yield) of the titlecompound as a white solid.

Step b: Preparation of4,6-dichloro-5-(2-chloro-6-fluorophenyl)-2-methylthiopyrimidine

To a suspension of4,6-dihydroxy-5-(2-chloro-6-fluorophenyl)-2-methylthiopyrimidine (2.57g, 8.96 mmol) in phosphorous oxychloride (25.7 ml, 276 mmol) was addedtri-n-propylamine (3.75 ml, 19.72 mmol) at room temperature undernitrogen atmosphere. After refluxing the reaction mixture at 140° C. for40 hours and cooling to room temperature the reaction mixture wasconcentrated in vacuo to afford a black oil. The crude product waspartitioned between ethyl acetate (250 ml) and water (250 ml) and theresulting biphasic mixture stirred vigrorously for 15 minutes. Theorganic phase was separated, washed with 2M aqueous hydrochloric acid(2×250 ml), saturated sodium bicarbonate solution (2×250 ml) andsaturated brine (250 ml). After drying over magnesium sulfate theorganic Phase was concentrated in vacuo to afford 2.3 g (79% yield) ofthe title compound as a dark brown solid.

EXAMPLE 47-49

TABLE III (synthesized analogously to Ex. 40-46) IA

melting point Ex. R¹ R⁵ R⁴ (° C.) 47 CF₃CH(CH₃) H C₆H₅—CH₂ 178 48 (S)- HCH₃O—C(═O)C(═CH₂)CH₂ 120-123 CF₃CH(CH₃) 49 CF₃CH(CH₃) H(CH₃CH₂O—C[═O])₂C(CH₃) 178 50 CF₃CH(CH₃) H CH≡C—CH₂ 185-186 51CF₃CH(CH₃) H thien-3-yl-CH₂ 68-72

Biological Investigations

A Determination of Minimum Inhibitory Concentration by Test Compounds inthe Serial Dilution Test with Pyricularia Oryzae

The MIC (Minimum Inhibitory Concentration) value, which indicates thelowest concentration of the active ingredient in the growth medium whichcauses a total inhibition of myecelial growth, is determined by serialdilution tests using Microtiter plates with 24 or 48 wells per plate.The dilution of the test compounds in the nutrient solution and thedistribution to the wells is carried out by a TECAN RSP 5000 RoboticSample Processor. The following test compound concentrations are used:0.05, 0.10, 0.20, 0.39, 0.78, 1.56, 3.13, 6.25, 12.50, 25.00, 50.00 and100.00 μg/ml. For preparation of the nutrient solution, V8 vegetableJuice (333 ml) is mixed with calcium carbonate (4.95 g), centrifuged,the supernatant (200 ml) diluted with water (800 ml) and autoclaved at121° C. for 30 min.

The inocula of Pyricularia Oryzae are added into the wells as sporesuspensions (50 μl; 5×10⁵/ml) or agar slices (6 mm) of an agar cultureof the fungus.

After 6-12 days incubation at temperatures of 18 to 25° C., the MICvalues are determined by visual inspection of the plates, as shown inTable IV

TABLE IV Example No. MIC [μg/ml] 3 3.13 4 >100 5 25 6 6.25 7 100

B Evaluation of In Vivo Fungicidal Activity of Test Compounds

Test compounds are dissolved in acetone and diluted with deionized water(95 parts water to 5 Parts acetone), containing 0.05% TWEEN 20®, apolyoxyethylene sorbitan monolaurate surfactant manufactured by AtlasChemical Industries, to give a concentration of 200 ppm.

The plants are sprayed with the test solutions, dried and inoculatedwith fungi later the saure day. When disease symptom development isoptimal, the plants are rated for disease control according to therating scale shown below. Each test contains inoculated treated plants,inoculated untreated plants and inoculated plants treated with referencefungicides. The data obtained are shown in Table V.

RATING SCALE Rating Range % Control 0  0 1  1-14 2 15-29 3 30-44 4 45-595 60-74 6 75-89 7 90-95 8 96-99 9 100

TARGETS Symbol Disease Pathogen AS Apple Scab Venturia inaequalis RBRice Blast Pyricularia grisea sp. oryzae GDM Grape downy mildewUniclnula necator

TABLE V Example AS RB GDM 2 0 0 0 3 7 5 7 4 5 3 3 5 9 4 0 6 9 6 3

C Evaluation of In Vitro Fungicidal Activity against Rhizoctonia solani

Test compounds are dissolved in acetone to give a concentration of 10ppm and added to individual cell walls (24-cell-well plates, Corning),which were previously filled with a suspension of ground fungal myceliumin a chemically defined growth medium After 3-7 days of incubation,inhibition of mycelial growth is recorded using the following scale: Thedata obtained are shown in Table VI.

RATING SCALE Rating Degree of Inhibition 0 None 3 slight 5 moderate 7severe 9 complete

TABLE VI Rhizoctonia solani Example (Rice sheath blight) 1 7 4 7 5 0 6 07 0 8 7

What is claimed is:
 1. A pyrimidine compound of formula I

in which R¹ represents C₁-C₁₀-alkyl, C₁-C₁₀-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₄-C₈-alkadienyl, C₁-C₁₀-alkoxy, C₃-C₈-cycloalkly,phenyl, tri-C₁--C₆-alkyl-silyl, formyl or C₁-C₁₀-alkoxy-carbonyl,wherein R¹ groups are unsubstituted or substituted by one to threegroups R^(a); R^(a) is halogen, nitro, cyano, hydroxy, or isC₁-C₁₀-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkenyl, C₁-C₁₀-haloalkyl,C₃-C₆-halocycloalkyl, C₁-C₁₀-alkoxy, C₁-C₁₀-haloalkoxy,C₁-C₁₀-alkoxycarbonyl, tri-C₁--C₄-alkyl-silyl, phenyl, halo- ordihalophenyl; R² represents phenyl or C₃-C₆-cycloalkyl, which areunsubstituted or substituted by one to three groups R^(a); R³ representshydrogen, halogen, or is C₁-C₁₀-alkyl, C₁-C₁₀-alkoxy, C₁-C₁₀-alkylthio,C₁-C₁₀-alkylamino or di-C₁-C₁₀-alkylamino, which are unsubstituted orsubstituted by one to three groups R^(a); R⁴ represents C₁-C₁₀-alkyl,C₂-C₆-alkenyl or C₂-C₆-alkynyl, which are unsubstituted or substitutedby one to three groups R^(a); and X represents O, S, NR⁵ or a singlebond, wherein R⁵ represents hydrogen, C₁-C₁₀-alkyl or C₁-C₁₀-haloalkyl;or R¹ and R⁵ together with the interjacent nitrogen atom form aheterocyclic ring selected from the group consisting of pyrrolidine,piperidine, tetrahydropyridine and azepane, which ring is optionallysubstituted by one or more C₁-C₁₀-alkyl groups.
 2. The compound offormula I defined in claim 1, in which R² represents a phenyl group offormula

wherein L¹ through L⁴ each independently represent hydrogen, fluorine,chlorine or methoxy.
 3. The compound of formula I defined in claim 1which is represented by formula IA

in which L¹ through L⁴ each independently represent hydrogen, fluorine,chlorine or methoxy.
 4. The compound defined in claim 1 in which R³represents chlorine.
 5. The compound defined in claim 1 in which R⁴represents C₁-C₆-alkyl or benzyl.
 6. A fungicidal composition whichcomprises a carrier and an effective amount of one or more compounds offormula I as defined in claim
 1. 7. A method of combating fungis at alocus which comprises treating the locus with an effective amount of oneor more compounds of formula I as defined in claim 1.